Method of enhancing memory or correcting memory deficiency with arylamido(and arylthiomido)-azabicycloalkanes

ABSTRACT

A method for improving memory or correcting memory deficiency is disclosed, utilizing compounds of the general formula: &lt;CHEM&gt; wherein each of n&lt;1&gt;, n&lt;2&gt;, n&lt;3&gt; and n&lt;4&gt; represent an integer of from zero to 3; each of R&lt;1&gt;, R&lt;2&gt;, R&lt;3&gt;, and R&lt;4&gt; independently represent a hydrogen atom, a loweralkyl or phehnyl group; R&lt;5&gt; represents a hydrogen atom or loweralkyl group; Ar represents a phenyl, substituted phenyl, pyridinyl, furanyl, thienyl, methoxy-1H-benzotriazolyl, indolinyl, methoxyindolinyl, methoxypyrimidinyl, amino-methoxypyrimadinyl, 1,3-benzodioxolyl, or naphthalenyl group; X represents oxygen or sulphur; the optical isomers; and the pharmaceutically acceptable acid addition salts, such as hydrates and alcoholates thereof. The dosage effective for this use is from 10 to 1000 nanograms/kg body weight.

FIELD OF INVENTION

This invention relates to a method of improving the memory of livinganimals with certain arylamidoazabicycloalkanes. The inventioncontemplates the treatment of memory deficiencies and disorders.

INFORMATION DISCLOSURE STATEMENT

Various chemicals such as physostigmine, arecholine, choline orpiracetam have been reported to facilitate memory in animals, KIRKOTHMER, ENCYCL. CHEM. TECHNOL., 3rd Ed. (1981) Vol. 15, pp 132-142 andANNUAL REPORTS IN MEDICINAL CHEMISTRY (1984) VOL. 19, PP 31-43. Thecardiovascular drug procainamide has been tested for learningenhancement activity in experimental animals of different ages and hasbeen said to improve learning deficits in aging rats KIRK OTHMER ibid p.139. Ergoloid Mesylates have been used in treatment of impaired mentalfunction in the elderly. The ergoloid mesylates may in some cases giverise to nausea during treatment for mental impairment and may possessα-adrenergic blocking activity. THE MERCK INDEX 10th Ed. 3596 andPHYSICIANS DESK REF., 38th Ed. 1984, pp 911-912. In contrast, certain ofthe compounds of the formula used in the present invention haveantinauseant properties and are not α-adrenergic blocking agents,cholinomimetics, cholinesterase inhibitors or stimulants.

2-Alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamidesand their use in a method for increasing gastric emptying andalleviating emesis, particularly emesis due to administration ofplatinum and anticancer drugs such as cisplatin are disclosed in U.S.Pat. No. 4,593,034. Certain of these2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides are also disclosed inFr. Patent 2.529.548 and European patent application 099.789A and theiruse as gastrointestinal motility accelerators and as potentiators formedicaments, especially analgesics such as aspirin and paracetamol isalso disclosed. Certain of the compounds are also disclosed as useful asanalgesics-antiphsychotics in Brit. patent application 2,125,398A.

Syntheses of certain N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides have beenreported by E. E. Mikhalina, et al., in KHIM-FARM. Zh. (1973) 7(8) p.20-24: C.A. 79 146358a. The compounds were reported to posses narcotic,nerve center blocking and hypotensive activity.

The compound4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethyl-benzamidehas been reported in U.S. Pat. No. 4,093,734 in a class of compoundssaid to be anxiolytics, anticonvulsants, antiemetics andantiulcerogenics.

Certain of the compounds encompassed by Formula I and useful in themethod of the present invention and exemplified byN-(7-octahydroindolizinyl)benzamides are disclosed by structure, methodof synthesis and characterization in U.S. Pat. No. 4,213,983 as beinguseful in treating gastrointestinal misfunctions. Still other compoundsof Formula I useful in the present invention and exemplified by4-amino-4-chloro-2-methoxy-N-[4'-α,β-(1'-aza-2'-α-phenyl-6'-α-N-bicyclo[4,3,0]decyl)benzamideand4-amino-5-chloro-2-methoxy-N-[7'β-(9'β-methyl-1'-aza-5'α-H-bicyclo[4,3,0]nonyl)]benzamideare disclosed by structure, method of synthesis and characterization inEuropean patent application 0067565A1 as dopamine antagonists fortreating impaired gastric motility.

The compounds of this invention are disclosed to be useful in enhancingmemory or correcting memory deficiency in U.S. Pat. No. 4,605,652.However, the dosages taught to be useful in that patent aresignificantly higher than the dose levels now found to be effective.

SUMMARY OF THE INVENTION

The arylamidoazabicycloalkanes useful in the method of this inventionfor improving memory or correcting memory deficiency have the generalformula: ##STR2## wherein,

n¹, n², n³

and n⁴ =0 to 3

R¹, R², R³, and R⁴ =H, loweralkyl or phenyl

R⁵ =H or loweralkyl

X=O or S

Ar= ##STR3##

Y=H, loweralkoxy, loweralkylthio, halo, trifluoromethyl, amino,loweralkylamino, dialkylamino, arylamino, acyl, aminosulfonyl,loweralkylsulfonyl, nitro or aminocarbonyl;

m, 1 to 3

Z=amino, loweralkylamino or diloweralkylamino;

the optical isomers; and the pharmaceutically acceptable acid additionsalts, including hydrates and alcoholates thereof.

The compounds are administered using usual pharmaceutical procedures andcarriers as described hereinbelow.

In the further definition of symbols and in the formulas hereof andwhere they appear elsewhere throughout this specification and in theclaims, the terms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified,includes straight and branched chain radicals of up to eight carbonsinclusive and is exemplified by such groups as methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyland octyl radicals and the like. The term "loweralkoxy" has the formula-0-loweralkyl.

The term "halo" or "halogen" when referred to herein includes fluorine,chlorine, bromine and iodine unless otherwise stated.

"Pharmaceutically acceptable salts" include acid addition salts andhydrates and alcoholates thereof which are physiologically compatible inliving animals. The acid addition salts may be formed by either strongor weak acids. Representative of strong acids are hydrochloric,hydrobromic, sulfuric and phosphoric acids. Representative of weak acidsare fumaric, maleic, mandelic, tartaric, citric, oxalic, succinic,hexamic and the like.

DETAILED DESCRIPTION OF THE INVENTION

The memory enhancing agents of Formula I above, useful in the method ofthis invention, may be prepared generally by methods for preparing suchamides as described in U.S. Pat. No. 4,593,034, in French Patent2.529.548, European patent application ED 67565 and U.S. Pat. No.4,213,984. Two principal general methods, A and B, are illustrated inthe following equations for preparation of arylamidoazabicycloalkanes:

Method A using an acid chloride ##STR4##

Method B, using 1,1'-carbonyldiimidazole ##STR5##

Compounds of Formula I wherein Ar has a primary amino substituent mayalso be prepared from a compound prepared by Methods A or B wherein thesubstituent is nitro by catalytic reduction of the nitro group to theamino group. Alternatively, such amino compounds may be prepared byMethod A, utilizing a starting aroyl halide wherein the aminosubstituent has been protected and thereafter deprotected.

Amide formation may also be accomplished by heating an arylacid esterwith the amine in an inert solvent.

The acid addition salts of compounds of Formula I may be prepared inconventional manner by reacting a free base with a pharmaceuticallyacceptable acid as described above.

The free base of an acid addition salt may be obtained by partitioningthe salt in an organic solvent such as methylene chloride and a weakbasic aqueous solution and thereafter separating and evaporating theorganic solvent layer.

Compounds in this invention may exist in racemic form or they may beseparated into optical isomers by procedures described in Fr. Patent2,529,548. Thus, this invention encompasses racemic and optically activeforms.

PREPARATION OF THIOARYLAMIDES

The preparation of the thioarylamide compounds encompassed by Formula Imay be accomplished by mixing and reacting a benzamide compound ofFormula I with a mixture of phosphorus pentasulfide (P₂ S₅) andpotassium sulfide (K₂ S) or by mixing and reacting 3-aminoquinuclidinewith an appropriately substituted arylaldehyde and sulfur. The reactionsequences are illustrated by the following equations: ##STR6##

A preferred group of compounds encompassed by Formula I useful in themethod of this invention have the formula: ##STR7## wherein Am is amino(i.e., --NH₂) or methylamino. The compound,4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide andits pharmaceutically acceptable salts as defined above is particularlypreferred.

The following examples are provided merely by way of illustrating themethods of preparation of compounds useful in the method of theinvention and are not to be construed as limiting in nature.

EXAMPLE 1

4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide,fumarate [1.1].

In a closed system equipped with an oil bubbler, 30 ml oftetrahydrofuran was added to a mixture of4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g (0.010 mole) and1,1'-carbonyldiimidazole, 1.62 g (0.010 mole) with stirring. Whenevolution of carbon dioxide ceased, nitrogen was bubbled through thereaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 1.26 g,(0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the stirredreaction mixture and stirring at room temperature continued for 3 hrs.TLC analysis (3% conc. ammonium hydroxide solution in methanol) showedsome product formation. The mixture was heated at reflux temperature for18 hours and then concentrated to an oil. TLC analysis showed thepresence of the product, imidazole, and 3-aminoquinuclidine. The oil wasdissolved in methylene chloride (75 ml) and washed twice with 50 mlportions of aqueous sodium bicarbonate solution. The methylene chloridelayer was dried over anhydrous magnesium sulfate and concentrated toyield 2.0 g (67%) of a glassy amorphous solid, the free base of thetitle compound.

In another reaction on a 0.020 mole scale, 5.18 g (83.8%) of the productas the free base was obtained.

The products were combined, dissolved in methanol (20 ml) and thesolution and treated with a solution of fumaric acid (2.73 g) inmethanol (50 ml). Absolute ether was added to precipitate the salt whichwas collected by filtration and recrystallized from methanol-ater(200:20) with isopropyl ether added to the point of incipientcloudiness. The recrystallized salt (5.38 g) melted at 223°-225° C.

Analysis: Calculated for C₁₉ H₂₄ N₃ O₆ Cl: C, 53.59; H, 5.68; N, 9.89Found: C, 53.35; H, 5.72; N, 9.95

EXAMPLE 2

4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide,hydrochloride, hydrate (1:1:1).

To an isopropyl alcohol solution of the free base of the title compoundsuch as was obtained by the procedure midway through Example 1 is addedin equal molar amount of 37% (conc.) hydrochloric acid. A salt isseparated by addition of acetone followed by filtration which isrecrystallized from acetone-water to give the title compound, m.p.158°-160° C.

EXAMPLE 3

N-(1-Azabicyclo[2.2.2]oct-3-yl-5-chloro-2-methoxy-4-methylaminobenzamide,fumarate [1.1].

To a mixture of 1,1'-carbonyldiimidazole, 1.23 g (0.00756 mole) and5-chloro-2-methoxy-4-methylaminobenzoic acid, 1.63 g (0.00756 mole) wasadded 50 ml of tetrahydrofuran. Nitrogen was bubbled into the solutionfor 30 minutes to remove any carbon dioxide that was present. To thesolution was added 3-aminoquinuclidine, 0.95 g, (0.00756 mole) in oneportion, and the reaction mixture was stirred at ambient temperature for16 hours. The reaction mixture was concentrated to an oil which wasshown to be 1:1 mixture of the free base of the product and imidazole.The mixture was dissolved in 20 ml methanol and treated with a solutioncontaining 0.47 g fumaric acid in 20 ml of hot methanol. Upon cooling,1.52 g of white solid formed. Recrystallization from water-methanol gave0.84 g of the product as a white solit; m.p. 237°-238° C.

Analysis: Calculated for C₂₀ H₂₆ N₃ O₆ Cl: C, 54.61; H, 5.96; N, 9.55Found: C, 54.61; H, 5.98; N, 9.51

EXAMPLE 4

N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-4-(methylamino)-benzamide,hydrochloride (1:1).

To an isopropyl alcohol solution of the free base of the title compound,such as was obtained by the procedure of Example 3, is added an equalmolar amount of 37% (conc.) hydrochloric acid. The crude salt isseparated by filtration and recrystallized from ethanol-water to givethe title compound, m.p. 255°-258° C.

EXAMPLE 5

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide, fumarate[1.1]hemihydrate.

In a closed system equipped with an oil bubbler, a solution of2-methoxybenzoyl chloride, 2.76 g (0.0016 mole) in 50 ml absolute etherwas added dropwise over 10 min to a stirred solution of3-aminoquinuclidine, 1.81 g (0.0144 mole) in 100 ml absolute ether.After the addition was completed, the mixture was stirred at roomtemperature for an additional 2 hrs. The solid hydrochloride salt wascollected by filtration under nitrogen. The salt (3.83 g) was dissolvedin sodium bicarbonate solution and extracted twice with 25 ml portionsof methylene chloride. The extract was dried over magnesium sulfate andconcentrated to yield 1.25 g clear oil (33.3%). TLC analysis (3% conc.ammonium hydroxide in methanol) showed the free base to be pure. Asolution of 1.17 g of the free base in 5 ml methanol was treated wiht asolution of 0.52 g fumaric acid in 10 ml methanol. Isopropyl ether wasadded to give approximately 100 ml of solution from which the fumaratesalt precipitated. The salt was collected under nitrogen and dried in avacuum oven at 60° C. overnight. NMR and elemental analyses showed thatthe product was a hemihydrate.

Analysis: Calculated for C₁₉ H₂₅ N₂ O₆.5 : C, 59.21; H, 6.54; N, 7.27Found: C, 59.18; H, 6.30; N, 7.25

EXAMPLE 6

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide hydrochloride[1:1].

A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.0349),2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodiumcarbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroformwas stirred rapidly to achieve good mixing of the 2 layers for 20 hrs.The chloroform layer was then separated, washed with water, dried overanhydrous magnesium sulfate, and concentrated to an impure oil. The oilwas triturated twice with 20 ml portions of petroleum ether to removesome impurities. The oil was then dissolved in ether and filtered toremove a small amount of insoluble material. The filtrate was treatedwith ethereal hydrogen chloride and the resulting salt collected toyield 2.70 g (23.7% yield) white solid. The salt was recrystallized fromethanol-isopropyl ether. Further recrystallization from methanol-ethylether yielded a white solid, m.p. 211°-212° C. The NMR analysis wassatisfactory.

Analysis: Calculated for C₁₆ H₂₃ N₂ O₃ Cl: C, 58.80; H, 7.09; N, 8.57Found: C, 58.38; H, 7.13; N, 8.44

EXAMPLE 7

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide, sulfate [1:1].

In a closed system equipped with a oil bubbler, a solution of2,4-dimethoxybenzoyl chloride, 13.08 g, (0.0652 mole) in 200 ml absoluteether was added dropwise over 30 minutes to a stirred solution of3-aminoquinuclidine, 7.80 g, (0.0619 mole) in 200 ml absolute ether. Themixture was stirred overnight, and the solid hydrochloride salt of theproduct was filtered under nitrogen. The material was dried in a vacuumoven at 40° C. to give 18.70 g (92%). A 2.94 g (0.009 mole) portion ofthe hydrochloride salt in 20 ml methanol was treated with a solution ofsodium methoxide prepared from 0.23 g (0.010 mole) sodium metal and 10ml methanol. After standing a few minutes, the mixture was filtered andthe filtrate concentrated on a rotary evaporator, and the residue wastriturated with 75 ml methylene chloride. After filtering to remove someinsoluble solids, the filtrate was concentrated to yield 2.53 g of thefree base of the title compound (97% recovery from the hydrochloridesalt). The free base was dissolved in 100 ml acetone and concentratedsulfuric acid (0.483 ml) added dropwise with stirring. The solid thatformed was collected under nitrogen to give 2.76 g of the salt whichrecrystallized from methanol-isopropyl ether and dried in a vacuum ovenat 60° C. for 2 hrs and then overnight at 78° C.; m.p. 223°-225° C.

Analysis: Calculated for C₁₆ H₂₄ N₂ O₇ S: C, 49.47; H, 6.23; N, 7.23Found: C, 49.41; H, 6.30; N, 7.25

EXAMPLE 8

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide, fumarate[1:1.5].

In a closed system equipped with an oil bubbler, tetrahydrofuran, 100ml, was added to a misture of 2,4-dimethoxybenzoic acid, 3.64 g (0.020mole) and 1,1'carbonyldimidazole, 3.24 g (0.020 mole). No evolution ofcarbon dioxide was observed and after stirring for 3 hrs, TLC (ethylacetate) and mass spectral analysis showed that the starting materialhad reacted to form (2,4-dimethoxybenzoyl)imidazole and imidazole. Asolution of 3-aminoquinuclidine, 2.52 g (0.020 mole) in 10 mltetrahydrofuran was added to the mixture, and the solution was heated toreflux temperature for 1 hr and then allowed to stand overnight at roomtemperature. A solution of fumaric acid, 2.32 g (0.020 mole) in 50 mlmethanol was added to the reaction mixture. Tetrahydrofuran was addeduntil the solution became slightly turbid. The solution was chilled in arefrigerator. The solid which precipitated from solution was collectedby filtration and found to be a fumarate salt of 3-aminoquiniculidine.The filtrate was concentrated to an oil and triturated withtetrahydrofuran. The solid precipitate which formed on standing wasfiltered and shown by TLC (3% concentrated ammonium hydroxide inmethanol) to be the desired product plus traces of imidazole and3-aminoquinuclidine. Recrystallization from methanol-isopropyl ethergave 5.41 g white crystalline solid (67% yield calculated as themonofumarate). NMR and elemental analysis showed the salt to containless than one equivalent of fumaric acid. The salt was dissolved inboiling methanol (50 ml) and treated with an additional 0.77 g (0.0066mole) fumaric acid in 10 ml hot methanol. Isopropyl ether was addeduntil the hot solution became turbid. The solid obtained on cooling wascollected, recrystallized from methanol-isopropyl ether and dried in avacuum oven at 78° C. overnight. NMR and elemental analysis showed thesalt to be a 1.5 fumarate, m.p. 192°-192.5° C.

Analysis: Calculated for C₂₂ H₂₈ N₂ O₉ : C, 56.89; H, 6.08; N, 6.03Found: C, 56.81; H, 6.13; N, 6.04

EXAMPLE 9

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propoxybenzamide hydrochloride [1:1].

To a solution of 3.82 g (0.0192 mole) of 3-aminoquinuclidinedihydrochloride in about 25 ml of carbon dioxide-free water was added 8g (0.025 mole) of barium hydroxide octahydrate. The mixture was warmedfor 5 minutes and then dried to a powder on a rotary evaporator. Whileprotecting from contamination with carbon dioxide in the atmosphere, thepowder was extracted in sequence with hot benzene and a 1:1 mixture ofbenzene-methylene chloride solution. The combined extracts were driedover magnesium sulfate and the mixture filtered. To the filtrate withagitation was added dropwise a solution of 3.4 g (0.0171 mole) of2-propoxybenzoyl chloride in 50 ml of methylene chloride. The mixturewas warmed on a steam bath to evaporate about 75% of the methylenechloride. Ligroin (60-110) was added and the mixture solidified. Thesolid was recrystallized from anhydrous ethyl alcohol to give 3.9 g(62.0%), m.p. 210°-211° C.

Analysis: Calculated for C₁₇ H₂₅ N₂ O₂ Cl: C, 62.86; H, 7.75; N, 8.62Found: C, 62.62; H, 7.59; N, 8.54

EXAMPLE 10

N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-naphthalenecarboxamide,hydrochloride [1:1].

A solution of 1.69 g (0.00768 mole) of 3-methoxy-2-naphthoic acidchloride in 15 ml of methylene chloride was added dropwise to a stirredsolution of 0.97 g (0.00768 mole) of 3-aminoquinuclidine in 25 ml ofmethylene chloride in a closed system equipped with an oil bubbler. Thereaction mixture was stirred overnight at ambient temperature, and thenconcentrated to give an off-white glassy solid. Two recrystallizationsfrom methanol-isopropyl ether gave 1.95 g (73.4%) of the product as anoff-white solid which was vacuum dried at ambient temperature, m.p.248°-252° C.

Analysis: Calculated for C₁₉ H₂₃ N₂ O₂ Cl: C, 65.79; H, 6.68; N, 8.08Found: C, 65.40; H, 6.72; N, 8.01

EXAMPLE 11

4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxythiobenzamidefumarate.

One half mole of4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamidefumarate is partitioned between dilute sodium hydroxide and 400 ml ofbenzene. The benzene solution is dried with sodium sulfate and distilledto a volume of 250 ml. To this is added a finely-ground mixture of 9 gof phosphorous pentasulfide and 9 g of potassium sulfide. The mixture isrefluxed for 4 hr and an additional 9 g of phosphorous pentasulfide isadded and reflux continued for 2 hr. The benzene is decanted off. Thesolid is dissolved in a suitable solvent and reacted with fumaric acidto give the title compound.

EXAMPLE 12

N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamide hydrochloride hydrate[1:1:0.75].

A solution of 3-aminoquinuclidine dihydrochloride (5.0 g, 0.0246 mole)in ca. 15 ml methanol/5 ml water was treated with barium hydroxideoctahydrate (9.0 g, 0.0286 mole), warmed over steam for ca 10 min, thentaken to dryness on the rotary evaporator at 40°-45° C./35 mm. Theresultant dry powder was repeatedly extracted with ca 6×50 ml drytetrahydrofuran. The tetrahydrofuran solution was concentrated byboiling until an 80-90 ml volume remained. This clear solution was addeddropwise with stirring to a hot solution of 4-nitrobenzoyl chloride(4.36 g, 0.235 mole) in benzene. The solid produced was recrystallizedfrom anhydrous methanol several times to yield 5.13 g of solid, meltingat 277°-279° C. Microanalysis and NMR showed 0.75 mole of water present.Mass spec. and IR were satisfactory, yield of title compound was 0.186mole (79.4%).

Analysis: Calculated for C₅₆ H₇₈ C₁₄ N₁₂ O₁₅ : C, 51.70; H, 6.04; N,12.92 Found: C, 51.48; H, 5.93; N, 12.91

EXAMPLE 13

4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide hydrochloride.

A solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamidehydrochloride (11.55 g, 0.037 mole) in 170 ml of 80% aqueous methanolwas shaken in a hydrogen atmosphere with a platinum oxide catalyst onthe Parr hydrogenator. The calculated volume of hydrogen was taken up inone hour. The catalyst was filtered off through Celite and the filtratetaken to dryness via rotary evaporator. Several recrystallizations ofthe colorless crystalline residue from 70% aqueous ethanol produced asolid melting above 310° C. NMR, MS, and IR supported the proposedstructure. Yield of title compound was 8.43 g (81.2%).

Analysis: Calculated for C₁₄ H₂₀ N₃ OCl: C, 59.67; H, 7.15; N, 14.91Found: C, 59.26; H, 7.11; N, 14.87

EXAMPLE 14

2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide dihydrochloride.

The free base was liberated from 3-aminoquinuclidine dihydrochloride(4.0 gm, 0.020 mole) using barium hydroxide and keeping the processunder dry nitrogen. The base thus obtained (0.018 mole) was dissolved indry tetrahydrofuran, treated with isatoic anhydride (2.04 gm, 0.018mole) and brought to reflux. The clear, dark brown solution within fiveminutes became tan-turbid. Reflux was contined for 1 hr, the excesstetrahydrofuran distilled off, and the residue added to boiling ethanol.A small amount of insoluble solid was filtered off. Chilling produced3.8 g (68%) crystalline amine base, m.p. 241°-243° C. The base wasconverted to the hydrochloride salt by reacting wiht etheralhydrogenchloride and recrystallized from either hot water-isopropanol ormethanol-methylethylketone (1:1) to yield a crystalline solid melting280.5°-283.5° C. NMR, MS, and IR were satisfactory. MW 318.249.

Analysis: Calculated for C₁₂ N₃ OC₁₄ H₂₁ : C, 52.84; H, 6.65; N, 13.20Found: C, 52.90; H, 6.54; N, 13.24

EXAMPLE 16

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-pyridinecarboxamide Fumarate [1.1].

Tetrahydrofuran (50 ml) was added to a mixture of picolinic acid (2.46g, 0.020 mole) and 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole) and themixture stirred in a closed system equipped with an oil bubbler untilevolution of carbon dioxide ceased. Nitrogen was then bubbled throughthe reaction mixture to sweep out any remaining carbon dioxide. 3Aminoquinuclidine (2.52 g, 0.020 mole) was added to the reaction mixturein one portion and the mixture heated at reflux temperature for 1 hrwhile continuing to saturate the mixture with nitrogen. After cooling,the mixture was concentrated to a brown oil containing the product,imidazole, and a small amount of 3-aminoquinuclidine. The oil wasdissolved in methylene chloride (50 ml) and washed 3 times with 50 mlportions of water. The methylene chloride solution was dried overanhydrous magnesium sulfate and concentrated to an oil. The oil wasdissolved in ether and filtered to remove a small quantity of insolublematerial. The filtrate was concentrated to give 2.38 g free base (51.4%)which was redissolved in 100 ml ether and treated with a solution offumaric acid (1.20 g) in 50 ml methanol and the mixture triturated toinduce crystallization. The solid salt was collected under nitrogen toyield 3.14 g of white solid. TLC analysis (3% conc. ammonium hydroxidesolution in methanol) showed only a trace of impurity. Mass spectrum(EI)-m/e (% relative intensity): 231 (19), 161 (16), 125 (22), 109 (80),106 (28) 98 (24), 96 (29), 79 (29), 78 (73), 70 (100), 45 (22), 42 (45),and 41 (20).

Analysis: Calculated for C₂₇ H₂₁ N₃ O₅ : C, 58.78; H, 6.09; N, 12.10Found: C, 58.58; H, 6.10; N, 12.04

EXAMPLE 17

N-(1-Azabicyclo[2.2.2]oct-3-yl)benzamide, Fumarate [1:1].

In a closed system equipped with an oil bubbler, a solution of benzoylchloride (3.51 g, 0.020 mole) in 100 ml absolute ether was addeddropwise over 10 min to a stirred solution of 3-amino-quinuclidine (2.52g, 0.020 mole) in 100 ml absolute ether. After the addition wascompleted, the mixture was stirred an additional 1.5 hr, and the solidhydrochloride salt was filtered under nitrogen. The salt was dissolvedin methanol and treated with a solution of sodium methoxide preparedfrom 0.58 g sodium metal (0.025 ml) in 20 ml methanol. The mixture wasconcentrated and the residual material triturated with methylenechloride (50 ml), filtered, and the filtrate concentrated to give ayellow solid. The solid was triturated with a small amount of acetoneand then with 50 ml boiling toluene. The resulting solution was decantedaway from some insoluble gummy material. Isooctane was added to the hottoluene solution until the solution was turbid. After standingovernight, the solid free base was collected (2.23 g). The filtrate wasconcentrated and the residual solid recrystallized fromtoluene-isooctane to yield an additional 0.35 g of the free base, m.p.159°-160° C., total yield 2.58 g (56%). The free base was dissolved in100 ml acetone and treated with a solution of fumaric acid (1.30 g,0.0112 mole) in 30 ml methanol. The solution was concentrated to give asolid residue which was recrystallized from methanol-isopropyl ether togive 3.03 g of the product, m.p. 187°-190° C. Mass spectrum (E.I.) m/e(% relative intensity) 230 (14), 125 (16), 109 (76)m 105 (90), 98 (23),96 (21), 84 (17), 77 (69), 79 (100), 51 (23), 95 (25), 42 (42).

Analysis: Calculated for C₁₈ H₂₂ N₂ O₅ : C, 62.42; H, 6.40; N, 8.09Found: C, 62.01; H, 6.46; N, 7.99

EXAMPLE 18

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-furancarboxamide hydrochloride.

In a closed system equipped with an oil bubbler, a solution of3-amino-quinuclidine (2.52 g, 0.020 mole) in 10 ml anhydrous ether wasadded dropwise to a stirred solution of furoyl chloride (3.26 g, 0.025mole) in 100 ml anhydrous ether. After the addition was completed (5min), the mixture was stirred an additional hour and the solid collectedunder nitrogen to give 4.73 g (73.7% yield) of the hydrochloride salt.TLC (3% concentrated ammonium hydroxide in methanol) showed a smallamount of impurity which was not removed by recrystallization. The saltwas dissolved in 20 ml of water, basified with 6N sodium hydroxidesolution, and extracted three times with 20 ml portions of methylenechloride. The combined extract was dried over magnesium sulfate andconcentrated to yield 2.37 g viscous yellow oil. The oil was dissolvedin 20 ml methanol, treated with excess ethereal hydrogen chloridesolution and diluted with 100 ml anhydrous ether. The salt crystallizedon trituration and was collected under nitrogen to give 1.84 g off-whitesolid. This solid was recrystallized from methanol-isopropyl ether otgive 1.63 g white solid, m.p. 249°-251° C. Mass spectrum (E.I.)-m/e (%relative intensity): 220 (19), 109 (74), 96 (29), 95 (100), 84 (14), 70(83), 72 (52), 42 (20), 39 (47).

Analysis: Calculated for C12H17N202Cl: C, 56.14; H, 6.67; N, 10.91Found: C, 56.06; H, 6.69; N, 10.77

EXAMPLE 19

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzamide, Monohydrochloride.

In a closed system, a solution of 3-aminoquinuclidine (2.52 g, 0.020mole) in 10 ml anhydrous ether was added dropwise to a stirred solutionof 2-fluorobenzoyl chloride (3.13 g, 0.020 mole) in 100 ml anhydrousether. After the addition was complete, the mixture was stirred anotherhour and the solid product (as the hydrochloride salt) was collected byfiltration under nitrogen to give 4.75 g (84%). TLC analysis (3% conc.ammonium hydroxide in methanol) showed the presence of3-aminoquinuclidine. The salt was dissolved in 10 ml water, basifiedwith 6N sodium hydroxide solution, and extracted three times with 50 mlportions of methylene chloride. The combined extract was dried overmagnesium sulfate and concentrated to give 3.67 g of the product as thefree base. Recrystallization from toluene-isooctane gave 2.33 g of awhite solid (some toluene insoluble material was removed by decantingthe hot toluene solution). The solid free base was dissolved in 10 mlmethanol, treated with excess ethereal hydrogen chloride and 100 mlisopropyl ether was added. The salt separated from solution as an oil,but crystallized on trituration. The white solid was collected undernitrogen to give 2.60 g; m.p. 233°-234° C. Mass spectrum (E.I.) m/e (%relative intensity): 248 (15), 125 (13), 123 (100), 109 (80), 96 (24),95 (45), 84 (14), 75 (19), 70 (64), 42 (44), 41 (18).

Analysis: Calculated for C₁₄ H₁₈ N₂ OFCl: C, 59.05; H, 6.37; N, 9.84Found: C, 58.78; H, 6.40; N, 9.86

EXAMPLE 20

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-thiophenecarboxamideMonohydrochloride.

Tetrahydrofuran (30 ml) was added with stirring to a mixture of2-thiophene carboxylic acid (2.56 g, 0.020 mole) and1,1'-carbonyldiimidazole (3.24 g, 0.020 mole). When solution of carbondioxide ceased, nitrogen was bubbled through the solution for 1 hr tofree the solution of carbon dioxide. 3-Aminoquinuclidine (2.52 g, 0.020mole) was added in one portion and the mixture heated to refluxtemperature for one hour while continuing to saturate the reactionmixture with nitrogen. After cooling, the mixture was concentrated, theresidual oil dissolved in 40 ml methylene chloride, and washed threetimes with 20 ml portions of water. The methylene chloride solution wasdried over magnesium chloride and concentrated to yield 2.57 g (54.4%)gummy white material. The amide was dissolved in a methanol-ethermixture treated with ethereal hydrogen chloride and diluted with ether,causing the salt to separate an oil which crystallized on trituration.The salt was collected under nitrogen (2.22 g) and recrystallized frommethanol-isopropyl ether to give 1.81 g white crystalline solid, m.p.245°-246° C. Mass spectrum (E.I.)-m/e (% relative intensity): 236 (17),125 (19), 111 (100), 109 (65), 96 (23), 84 (18), 83 (24), 82 (17), 70(84), 72 (45), 41 (20), 39 (43).

Analysis: Calculated for C₁₂ H₁₇ N₂ OSCl: C, 52.84; H, 6.28; N, 10.27Found: C, 52.88; H, 6.34; N, 10.36

EXAMPLE 21

N-(1-Azabicyclo[2.2.2]oct-3-yl)2,6-dimethoxybenzamide Monohydrochloride.

In a closed system equipped with an oil bubbler, a solution of2,6-dimethoxybenzoyl chloride (1.89 g, 0.0095 mole) in 20 ml diethylether was added dropwise to a stirred solution of 3-aminoquinuclidine(1.26 g, 0.010 mole) in 50 ml of diethyl ether. After the addition wascompleted, the reaction mixture was stirred for 15 min, and theprecipitate that had formed was filtered under nitrogen. The wet(hygroscopic) solid was immediately recrystallized frommethanol-isopropyl ether to give 1.85 g (60%) of the product. Thematerial was vacuum dried for 4 hr at 98° C., m.p. 266°-268° C.

Analysis: Calculated for C₁₆ H₂₃ N₂ O₃ Cl: C, 58.80; H, 7.09; N, 8.57Found: C, 58.44; H, 7.17; N, 8.51

EXAMPLE 22

N-(1-Azabicyclo[2.2.2]oct-3-yl)-1H-indole-5-carboxamide.

Tetrahydrofuran (50 ml) was added to a mixture of indole-5-carboxylicacid (2.42 g, 0.016 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015mole). The mixture was stirred for 1 hr while nitrogen was bubbledthrough the solution to remove the carbon dioxide that was evolved. Then3-aminoquinuclidine (1.89 g, 0.015 mole) was added in one portion, andthe mixture was stirred for 60 hr at room temperature. The solid productwas collected by filtration to yield 3.75 g (86.8%). Recrystallizationfrom methanol-isopropyl ether (with chilling) gave 1.89 g of the productas an off-white solid; m.p. 293°-295° C. The solid was vacuum dried at82° C. for 16 hr, m.p. 293°-295° C.

Analysis: Calculated for C₁₆ H₁₉ N₃ O: C, 71.35; H, 7.11; N, 15.60Found: C, 70.96; H, 7.15; N, 15.38

EXAMPLE 23

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methoxy-5-(methyl-sulfonyl)benzamide,Monohydrochloride.

A solution of 3-aminoquinuclidine (1.50 g, 0.0119 mole) in 20 ml oftetrahydrofuran was added dropwise to a stirred solution of2-methoxy-5-methanesulfonylbenzoyl chloride (2.95 g, 0.0119 mole) in 100ml tetrahydrofuran. The mixture was stirred at ambient temperature for20 hr and filtered to yield 4.00 g (89.7%) of the product as thehydrochloride salt. The material was heated in 100 ml of boilingabsolute ethanol and 50 ml methanol was added to give a clear solution.The solution was evaporated to a volume of 100 ml and cooled. Theprecipitate which formed was collected by filtration and vacuum dried at110° C. for 8 hr; m.p. 219°-221° C.

Analysis: Calculated for C₁₆ H₂₃ N₂ O₄ SCl: C, 51.26; H, 6.18; N, 7.47Found: C, 51.19; H, 6.6; N, 7.35

EXAMPLE 24

N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-bromo-2,4-dimethoxybenzamideMonohydrochloride.

A solution of 3-aminoquinuclidine (1.12 g, 0.0089 mole) in 20 mltetrahydrofuran was added dropwise to a stirred solution of5-bromo-2,4-dimethoxybenzoyl chloride (2.50 g, 0.0089 mole) in 100 mltetrahydrofuran. The mixture was stirred at ambient temperature for 65hr, and the solid was collected by filtration to yield 2.77 g.Recrystallization from methanol-isopropyl ether gave 1.45 g (40.2%),m.p. 240°-243° C.

Analysis: Calculated for C₁₆ H₂₁ N₂ O₃ Br: C, 47.37; H, 5.47; N, 6.90Found: C, 47.23; H, 5.62; N, 6.85

EXAMPLE 25

N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-methoxybenzamide, Monohydrochloride.

In a closed system, a solution of 3-methoxybenzoyl chloride (7.18 g,0.04206 mole) in 30 ml ether was added dropwise to a stirred solution of3-aminoquinuclidine (5.30 g, 0.04206 mole) in 100 ml of ether. Thereaction mixture was stirred at ambient temperature for 16 hr. The solidhydrochloride salt was collected under nitrogen and dried in vacuo atambient temperature to give 11.12 g (87.1%) of the product. The materialwas recrystallized from absolute ethanol-isopropyl ether to give 7.69 g.The product was vacuum dried for 20 hr over refluxing ethanol, and thenfor 24 hr over refluxing isooctane; m.p. 214°-215° C.

Analysis: Calculated for C₁₅ H₂₁ N₂ O₂ Cl: C, 60.70; H, 7.13; N, 9.44Found: C, 60.45; H, 7.15; N, 9.40

EXAMPLE 26

N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-fluorobenzamide, Monohydrochloride.

In a closed system, a solution of 3-fluorobenzoyl chloride (7.93 g,0.050 mole) in 30 ml ether was added dropwise to a stirred solution of3-aminoquinuclidine (6.3 g, 0.050 mole) in 100 ml ether. After theaddition was completed, the mixture was stirred at ambient temperaturefor 16 hr. The solid hydrochloride salt was collected under a nitrogenatmosphere and vacuum dried for 2 hr, to yield 13.11 g (92.1%). The saltwas recrystallized from absolute ethanol-isopropyl ether to give 8.87 gof a white solid. The material was recrystallized from ethanol, andvacuum dried for 12 hr at 70° C., m.p. 257°-258° C.

Analysis: Calculated for C₁₄ H₁₈ N₂ OFCl: C, 59.05; H, 6.37; N, 9.84Found: C, 59.05; H, 6.41; N, 9.80

The preparations of certain compounds encompassed by Formula I anduseful in the present invention listed in the following Example 27 a ton are demonstrated and illustrated by structure in U.S. Pat. No.4,213,983.

EXAMPLE 27 a-n

(a) 4-Acetylamino-4-chloro-2-methoxy-N-(2-quinolizidinyl)benzamide.(Compound identified in Ex. 1 of U.S. Pat. No. 4,213,983).

(b) 4-Amino-5-chloro-2-methoxy-N-(2-quinolizidinyl)benzamide. (Compoundidentified in Ex. 2 of U.S. Pat. No. 4,213,983).

(c)4-Acetylamino-5-chloro-2-methoxy-N-(7-octahydroindolizidinyl)benzamide.(Compound identified in Ex. 3 of U.S. Pat. No. 4,213,983).

(d) 4-Amino-5-chloro-2-methoxy-N-(7-octahydroindolizidinyl)benzamide.(Compound identified in Ex. 4 of U.S. Pat. No. 4,213,983).

(e) 4-Acetylamino-5-chloro-2-methoxy-N-(3-quinolizidinyl)benzamide.(Compound identified in Ex. 5 of U.S. Pat. No. 4,213,983).

(f) 4-Amino-5-chloro-2-methoxy-N-(3-quinolizidinyl)benzamide. (Compoundidentified in Ex. 6 of U.S. Pat. No. 4,213,983).

(g) 4-Acetylamino-5-chloro-2-methoxy-N-(1-quinolizidinyl)benzamide.(Compound identified in Ex. 7 of U.S. Pat. No. 4,213,983).

(h) 4-Amino-5-chloro-2-methoxy-N-(1-quinolizidinyl)benzamide. (Compoundidentified in Ex. 8 of U.S. Pat. No. 4,213,983).

(i)4-Acetylamino-5-chloro-2-methoxy-N-(2-pyrido[1,2-a]pyrazinyl)benzamide.(Compound identified in Ex. 11 of U.S. Pat. No. 4,213,983).

(j)4-Acetylamino-5-chloro-2-methoxy-N-(2-octahydroindolizinyl)benzamide.(Compound identified in Ex. 13 of U.S. Pat. No. 4,213,983).

(k) 4-Amino-5-chloro-2-methoxy-N-(2-octahydroindolizinyl)benzamide.(Compound identified in Ex. 14 of U.S. Pat. No. 4,213,983).

(l)4-Acetylamino-4-chloro-2-methoxy-N-(6-methyl-2-quinolizidinyl)benzamide.(Compound identified in Ex. 15 of U.S. Pat. No. 4,213,983).

(m) 4-Amino-5-chloro-2-methoxy-N-(6-methyl-2-quinolizidinyl)benzamide.(Compound identified in Ex. 16 of U.S. Pat. No. 4,213,983) and

(n) 4-Amino-5-chloro-2-methoxy-N-(6-methyl-2-quinolizidinyl)benzamide.(Compound identified in Ex. 17 of U.S. Pat. No. 4,213,983).

The preparation of certain compounds encompassed by Formula I and usefulin the present invention listed in the following Example 28 a to z andExample 29 a and b are demonstrated and illustrated by structure inEuropean patent application publication No. 0067565A1 as follows:

EXAMPLE 28 a-z

(a)4-Amino-5-chloro-2-methoxy-N-[4'α-β-(1'-aza-2'-α-phenyl-6'-α-H-bicyclo[4,3,0)decyl)]benzamide(compound identified in Example 5 of European 0067565).

(b)4-Acetamido-5-chloro-2-methoxy-N-[7'β-(9'β-methyl-1'aza-5α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 6 of European 0067565).

(c)4-Acetamido-5-chloro-2-methoxy-N-[7'α-(9'β-methyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 7 of European 0067565).

(d)4-Amino-5-chloro-2-methoxy-N-[7'β-(9'β-methyl-1'-aza-5'α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 8 of European 0067565).

(e)4-Amino-5-chloro-2-methoxy-N-[7'α-(9'β-methyl-1'-aza-5'-α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 9 of European 0067565).

(f)4-Acetamido-5-chloro-2-methoxy-N-[7'β-(9'α-methyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 10 of European 0067565).

(g)4-Amino-5-chloro-2-methoxy-N-[7'β-(9'α-methyl-1'-aza-5α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 11 of European 0067565).

(h)4-Acetamido-5-chloro-2-methoxy-N-[7'α-(9'-α-methyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 12 of European 0067565).

(i)4-Amino-5-chloro-2-methoxy-N-[n'α-(7'-α-(9'-α-methyl-1'-aza-5α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 13 of European 0067565).

(j)4-Acetamido-5-chloro-2-methoxy-N-[7'β-(9',9'dimethyl)-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 14 of European 0067565).

(k)4-Amino-5-chloro-2-methoxy-N-(7'β-(9,9'-dimethyl)-1'-aza-5'α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 15 of European 0067565).

(l)4-Acetamido-5-chloro-2-methoxy-N-[7'α-(9',9'-dimethyl-1'-aza-5'-.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 16 of European 0067565).

(m)4-Amino-5-chloro-2-methoxy-N-[7'α-(9',9'-dimethyl)-1'-aza-5'α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 17 of European 0067565).

(n)4-Acetamido-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamideIsomer I (compound identified in Example 18 of European 0067565).

(o)4-Amino-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamidemonohydrochloride, Isomer I (compound identified in Example 19 ofEuropean 0067565).

(p)4-Acetamido-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamideIsomer 2 (compound identified in Example 20 of European 0067565).

(q)4-Amino-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamideIsomer 2 (compound identified in Example 21 of European 0067565).

(r)4-Acetamido-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamideIsomer 3 (compound identified in Example 22 of European 0067565).

(s)4-Amino-5-chloro-2-methoxy-N-[7'β(9'-methyl-3'-phenyl-1'-axa-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide,Isomer 3 (compound identified in Example 23 of European 0067565).

(t)4-Amino-5-chloro-2-methoxy-N-[4'β-methyl-1'-aza-6'α-H-bicyclo[4,4,0]decyl)]benzamide(compound identified in Example 25 of European 0067565).

(u)4-Acetamido-5-chloro-2-methoxy-N-[4'α(7'β-methyl-1'-aza-6'.alpha.-H-bicyclo[4,4,0]decyl)]benzamidewith 10% 4'β isomer (mixture identified in Example 26 of European0067545).

(v)4-Amino-5-chloro-2-methoxy-N-[4'α-(7'β-methyl-1'-aza-6'α-H-bicylo[4,4,0]decyl)]benzamidewith 10% 4'β-isomer (mixture identified in Example 27 of European0067565).

(w)4-Acetamido-5-chloro-2-methoxy-N-[4'β(7'α-methyl-1'aza-6'.alpha.-H-bicyclo[4,4,0]decyl)]benzamide(compound identified in Example 28 of European 0067565).

(x)4-Amino-5-chloro-2-methoxy-N-[4'β-(7'α-methyl-1'-aza-6'α-H-bicyclo[4,4,0]decyl)]benzamide(compound identified in Example 29 of European 0067565).

(y)4-Acetamido-5-chloro-2-methoxy-N-[7'β(5'α-methyl-1'-aza-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 30 of European 0067565).

(z)4-Acetamido-5-chloro-2-methoxy-N-[7'β(9'α-ethyl-1'aza-5'-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 32 of European 0067565).

EXAMPLE 29 a-b

(a)4-Amino-5-chloro-2-methoxy-N-[7'β-(9'α-ethyl-1'-aza-5'α-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 33 of European 0067565).

(b)4-Acetamido-5-chloro-2-methoxy-N-[7'β-(9'α-isopropyl-1'-aza-5'.alpha.-H-bicyclo[4,3,0]nonyl)]benzamide(compound identified in Example 34 of European 0067565).

EXAMPLE 30

N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxy-1H-benzotriazole-5-carboxamide.

Following the procedure of Example 22,6-methoxy-1H-benzotriazole-5-carboxylic acid, 1,1'-carbonyldiimidazoleand 3-aminoquinuclidine are reacted to give the title compound.

EXAMPLE 31

N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-methoxy-1H-indole-5-carboxamide.

Following the procedure of Example 22, indole-6-methoxy-5-carboxylicacid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted togive the title compound.

EXAMPLE 32

N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(dimethylamino)-4-methoxy-5-pyrimidinecarboxamide.

Following the procedure of Example 22,2-(dimethyl-amino)-4-methoxy-5-pyrimidinecarboxylic acid,1,1'-carbonyl-diimidazole and 3-aminoquinuclidine are reacted to givethe title compound.

EXAMPLE 33

N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-methoxy-2-(methyl-amino)-5-pyrimidinecarboxamide.

Following the procedure of Example 22,4-methoxy-2-(methylamino)-5-pyrimidinecarboxylic acid,1,1'-carbonyl-diimidazole and 3-aminoquinuclidine are reacted to givethe title compound.

EXAMPLE 34

2-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-4-methoxy-5-pyrimidinecarboxamide.

Following the procedure of Example 22,2-amino-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazoleand 3-aminoquinuclidine are reacted to give the title compound.

EXAMPLE 35

N-(1-Azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide.

Following the procedure of Example 22, 1,3-benzodioxole-5-carboxylicacid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted togive the title compound.

PHARMACOLOGICAL TESTING (MARMOSET)

The procedure used to test the compound of Example 1,4-amino-N-(1-aza-bicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamidefumarate [1:1], was as follows:

Common male and female marmosets aged 15-18 months and weighing 300 to340 g were tested for performance in a discriminative learning task anda reverse learning task by using the Wisconsin General Test Apparatus.The Wisconsin General Test Apparatus (WGTA) was designed by Harlow in1949 (PSYCHOLOGICAL REVIEW 56: 51-65).

The WGTA is a structure in which an experimenter can present themarmoset with single trials of a learning task and assess itstrial-by-trial cumulative performance. It consists, essentially, of alarge, cubical enclosure containing a test board insert with small foodwells. One of the wells is baited with food and covered with aparticular visual stimuli. The marmoset on its cage is separated fromthe interior of the WGTA by an opaque shutter, which the experimenteropens at the beginning of each trial. When the shutter is open, theanimal can reach, through the bars of its cage, into the WGTA and cantouch the stimulus to claim the reward (when touched, stimulus is pulledaway via an attached length of cotton string). After the trial iscompleted, the shutter is closed and the experimenter reloads the wellthrough a trap door at the other end of the apparatus. The apparatus isarranged so that the animal cannot see the experimenter, although theexperimenter can view the animal via a smoked glass screen. Thisarrangement is important since it precludes the experimenter fromtransmitting signals of encouragement, disappointment, and the like,which might bias test results. The rewards used were confectioner'ssugar coated bread slices, broken into small cubes; malt loaf cubes; andcubes of bread soaked in syrup. In the initial shaping of test animalswith discriminative learning, they were trained to a criterion of 90/100correct responses, then 18/20, and finally 9/10 correct responses whenrepeated.

Four marmosets received 10 ng/kg of the compound of Example 1,subcutaneously, twice daily. At 10 ng/kg, the compound of Example 1 wasshown to increase the correct responding rate in both the discriminativeand reverse learning tasks. In the discriminative learning task, theaction of the compound of Example 1 was most marked in animals thatconsistently made more mistakes before reaching criterion (6consecutive, correct responses). All marmosets found the reverselearning task most difficult, and in all animals the compound of Example1 improved performance to such an extent that during drug treatmentanimals generally performed similarly in the discriminative and reverselearning tasks. Generally, therefore, following treatment with thecompound of Example 1, the number of trials to criterion in the reverselearning task was reduced from an order of 12-24 trials to 2-12 trials.Test data collected indicated that the compound of Example 1 markedlyimproves cognitive function in the marmoset.

PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions used in the method of this invention foradministration to animals and humans are comprised of, as activeingredients, at least one of the compounds of Formula I, according tothe invention, in association with a pharmaceutical carrier orexcipient. The compounds are thus presented in a therapeutic compositionfor oral, parenteral, subcutaneous, intramuscular, intraperitoneal,intravenous, or rectal administration. Thus, for example, compositionsfor oral administration can take the form of elixirs, capsules, tablets,or coated tablets containing carriers conveniently used in thepharmaceutical art. Suitable tableting excipients include lactose,potato and maize starches, talc, gelatin, stearic and silicic acids,magnesium stearate and polyvinyl pyrrolidones.

For parenteral administration, the carrier or excipient can be comprisedof a sterile parenterally acceptable liquid; e.g., water or arachis oilcontained in ampoules.

In compositions for rectal administration, the carrier can be comprisedof a suppository base; e.g., cocoa butter or a glyceride.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage forms according to the invention. It isonly necessary that the active ingredient constitute an effectiveamount; i.e., such that a suitable effective dosage will be consistentwith the dosage form employed in single or multiple unit doses. Theexact individual dosages, as well as daily dosages, will of course bedetermined according to standard medical principles under the directionof a physician or veterinarian. Generally, the pharmacology testssuggest an effective dose for humans will be in the range of about 10 to1000 nanograms/kg of body weight for a compound such as that of Example1 to produce memory enhancement in humans; for example, in impairedmemory of the elderly.

What is claimed is:
 1. A method for enhancing learning or memory inliving animals which comprises administering thereto from about 10 to1000 nanograms/kg of a compound selected from the group having theformula: ##STR8## wherein, n¹, n², n³ and n⁴ are zero to threeinclusive; R¹, R², R³, and R⁴ are hydrogen, loweralkyl or phenyl; R⁵ ishydrogen or loweralkyl; X is oxygen or sulfur; Ar is selected from##STR9## Y is hydrogen, loweralkoxy, loweralkylthio, halo,trifluoromethyl, amino, loweralkylamino, diloweralkylamino, acylamino,acyl, aminosulfonyl, nitro, or aminocarbonyl; m is one to threeinclusive; Z is amino, loweralkylamino, diloweralkylamino, and thepharmaceutically acceptable acid addition salts including hydrates andalcoholates thereof and the optical isomers.
 2. The method of claim 1wherein the compound used is4-amino-N-(azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-benzamide or apharmaceutically acceptable acid addition salt thereof.
 3. The method ofclaim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-4-methyl-aminobenzamideor a pharmaceutically acceptable acid addition salt thereof.
 4. Themethod of claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide or a pharmaceuticallyacceptable acid addition salt thereof.
 5. The method of claim 1 whereinthe compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-4-dimethoxybenzamide or apharmaceutically acceptable acid addition salt thereof.
 6. The method ofclaim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-4-propoxybenzamide or apharmaceutically acceptable acid addition salt thereof.
 7. The method ofclaim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-naphthalene-carboxamide or apharmaceutically acceptable acid addition salt thereof.
 8. The method ofclaim 1 wherein the compound used is4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxythiobenzamideor a pharmaceutically acceptable acid addition salt thereof.
 9. Themethod of claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-4-nitrobenzamide or a pharmaceuticallyacceptable acid addition salt thereof.
 10. The method of claim 1 whereinthe compound used is 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-benzamideor a pharmaceutically acceptable acid addition salt thereof.
 11. Themethod of claim 1 wherein the compound used is5-aminosulfonyl-N-(1-azabicyclo[2.2.2]oct-3-yl-2-methoxy-benzamide or apharmaceutically acceptable acid addition salt thereof.
 12. The methodof claim 1 wherein the compound used is2-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide or a pharmaceuticallyacceptable acid addition salt thereof.
 13. The method of claim 1 whereinthe compound used is N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide or apharmaceutically acceptable acid addition salt thereof.
 14. The methodof claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzamide or a pharmaceuticallyacceptable acid addition salt thereof.
 15. The method of claim 1 whereinthe compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2,6-dimethoxybenzamide or apharmaceutically acceptable acid addition salt thereof.
 16. The methodof claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxy-5-(methylsulfonyl)-benzamideor a pharmaceutically acceptable acid addition salt thereof.
 17. Themethod of claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-5-bromo-2,4-dimethoxybenzamide or apharmaceutically acceptable acid addition salt thereof.
 18. The methodof claim 1 wherein the compound used isN-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxybenzamide or a pharmaceuticallyacceptable acid addition salt thereof.
 19. The method of claim 1 whereinthe compound used is N-(1-azabicyclo[2.2.2]oct-3-yl)-3-fluorobenzamideor a pharmaceutically acceptable acid addition salt thereof.